The major goal of this multi-project proposal is to determine whether idiotype based vaccines can control in vivo infection by human immunodeficiency virus (HIV). There is strong evidence indicating that the cellular receptor for HIV is the CD4 molecule. Selected mouse monoclonal anti-CD4 reagents can block HIV binding to CD4. In addition, some anti-idiotypic antibodies (anti-Id) generated against mouse monoclonal anti-CD4 can bind HIV, presumably by mimicking the CD4 molecule. We have designed a comprehensive approach to examine the HIV-CD4 interaction and assess whether idiotype reagents which inhibit the virus-receptor binding reaction have vaccine potential in vivo. This approach integrates biological, molecular, and immunological investigations, predicated on the principal features of both the HIV and simian immunodeficiency virus (SIV) systems. Project 1 involves the generation of mouse monoclonal antibodies that recognize the human CD4 molecule and can block HIV-CD4 and/or SIV-CD4 interactions in vitro. In Project 2, chimeric CD4 molecules containing domains of both human CD4 and the murine CD4 analog, L3T4, will be generated and transfected into murine EL-4 cells. In addition, the variable regions of the blocking monoclonal anti-CD4 which recognize different CD4 epitopes will be subjected to sequence analysis. Mouse variable region - human constant region chimeric antibodies will also be generated. Project 3 proposes to generate anti-Id reagents against the various monoclonal anti-CD4 preparations in experimental animals. This anti-Id response will be assessed for anti-HIV activity. Project 4 will produce anti-CD4 idiotype- derived synthetic peptides from the variable region amino acid sequence of the various blocking monoclonal anti-CD4 preparations. Project 5 involves the generation of anti-Id to anti-HIV envelope glycoproteins. Project 6 is to assess the vaccine potential of the idiotype based reagents in the SIV-rhesus monkey model. Project 7 will involve further vaccine efficacy, and toxicity studies for HIV will be performed in a limited number of chimpanzees with selected idiotype based vaccine candidates. Finally, in Project 8, human clinical trials will be performed on AIDS patients using monoclonal anti-CD4 reagents for immunotherapy. The research projects are supported by a core laboratory for assessing HIV and SIV serology, along with in vitro neutralization assays. This multi-project proposal will provide insights into whether idiotype reagents may represent putative vaccine candidates for preventing HIV infection and/or AIDS.
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